Carrier particles for use in dry powder inhalers

ABSTRACT

A powder for use in a dry powder inhaler includes active particles and carrier particles for carrying the active particles. The powder further includes additive material (4) on the surfaces of the carrier particles to promote the release of the active particles from the carrier particles on actuation of the inhaler. The powder is such that the active particles are not liable to be released from the carrier particles before actuation of the inhaler. The inclusion of additive material (4) in the powder has been found to give an increased respirable fraction of the active material.

This application is a 371 of PCT GB9600215 filed Jan. 31, 1996.

This invention relates to carrier particles for use in dry powderinhalers. More particularly the invention relates to a method ofproducing such particles, to a dry powder incorporating the particlesand to the particles themselves.

Inhalers are well known devices for administering pharmaceuticalproducts to the respiratory tract by inhalation. Inhalers are widelyused particularly in the treatment of diseases of the respiratory tract.

There are a number of types of inhaler currently available. The mostwidely used type is a pressurised metered dose inhaler (MDI) which usesa propellant to expel droplets containing the pharmaceutical product tothe respiratory tract. Those devices are disadvantageous onenvironmental grounds as they often use CFC propellants, and on clinicalgrounds related to the inhalation characteristics of the devices.

An alternative device to the MDI is the dry powder inhaler. The deliveryof dry powder particles of pharmaceutical products to the respiratorytract presents certain problems. The inhaler should deliver the maximumpossible proportion of the active particles expelled to the lungs,including a significant proportion to the lower lung, preferably at thelow inhalation capabilities to which some patients, especiallyasthmatics, are limited. It has been found, however, that, whencurrently available dry powder inhaler devices are used, in many casesonly about 10% of the active particles that leave the device oninhalation are deposited in the lower lung. More efficient dry powderinhalers would give clinical benefits.

The type of dry powder inhaler used is of significant importance to theefficiency of delivery over a range of airflow conditions of the activeparticles to the respiratory tract. Also, the physical properties of theactive particles used affect both the efficiency and reproducibility ofdelivery of the active particles and the site of deposition in therespiratory tract.

On exit from the inhaler device, the active particles should form aphysically and chemically stable aerocolloid which remains in suspensionuntil it reaches a conducting bronchiole or smaller branching of thepulmonary tree or other absorption site preferably in the lower lung.Once at the absorption site, the active particle should be capable ofefficient collection by the pulmonary mucosa with no active particlesbeing exhaled from the absorption site.

The size of the active particles is important. For effective delivery ofactive particles deep into the lungs, the active particles should besmall, with an equivalent aerodynamic diameter substantially in therange of 0.1 to 5 μm, approximately spherical and monodispersed in therespiratory tract. Small particles are, however, thermodynamicallyunstable due to their high surface area to volume ratio, which providessignificant excess surface free energy and encourages particles toagglomerate. In the inhaler, agglomeration of small particles andadherence of particles to the walls of the inhaler are problems thatresult in the active particles leaving the inhaler as large agglomeratesor being unable to leave the inhaler and remaining adhered to theinterior of the inhaler.

The uncertainty as to the extent of agglomeration of the particlesbetween each actuation of the inhaler and also between differentinhalers and different batches of particles, leads to poor dosereproducibility. It has been found that powders are reproduciblyfluidisable, and therefore reliably removable from an inhaler device,when the particles have a diameter greater than 90 μm.

To give the most effective dry powder aerosol, therefore, the particlesshould be large while in the inhaler, but small when in the respiratorytract.

In an attempt to achieve that situation, one type of dry powder for usein dry powder inhalers may include carrier particles to which the fineactive particles adhere whilst in the inhaler device, but which aredispersed from the surfaces of the carrier particles on inhalation intothe respiratory tract to give a fine suspension. The carrier particlesare often large particles greater than 90μm in diameter to give goodflow properties as indicated above. Small particles with a diameter ofless than 10 μm may be deposited on the wall of the delivery device andhave poor flow and entrainment properties leading to poor doseuniformity.

The increased efficiency of redispersion of the fine active particlesfrom the agglomerates or from the surfaces of carrier particles duringinhalation is regarded as a critical step in improving the efficiency ofthe dry powder inhalers.

It is known that the surface properties of a carrier particle areimportant. The shape and texture of the carrier particle should be suchas to give sufficient adhesion force to hold the active particles to thesurface of the carrier particle during fabrication of the dry powder andin the delivery device before use, but that force of adhesion should below enough to allow the dispersion of the active particles in therespiratory tract.

In order to reduce the force of adhesion between carrier particles andactive particles, it has been proposed to add a ternary component. Inparticular, using carrier particles of lactose and active particles ofsalbutamol, it has been proposed to add particles of magnesium stearateor Aerosil 200 (trade name of Degussa for colloidal silicon dioxide) inan amount of 1.5% by weight based on the weight of the carrier particlesto a lactose-salbutamol mix.

The conclusion of that proposal, however, was that, although theadhesion between the carrier particles and the active particles wasreduced by the presence of the additive particles, the addition of theadditive particles was undesirable.

It is an object of the invention to provide a method for producingcarrier particles and a powder for use in dry powder inhalers, and toprovide carrier particles and a powder that mitigates the problemsreferred to above.

We have found that, contrary to the teaching of the prior art referredto above, the presence of additive particles which are attached to thesurfaces of the carrier particles to promote the release of the activeparticles from the carrier particles is advantageous provided that theadditive particles are not added in such a quantity that the activeparticles segregate from the surfaces of the carrier particles duringfabrication of the dry powder and in the delivery device before use.Furthermore, we have found that the required amount of the additiveparticles is surprisingly small and that, if a greater amount is added,there will be no additional benefit in terms of inhalation performancebut it will adversely affect the ability to process the mix. Therequired amount of additive particles varies according to thecomposition of the particles--in the case where the additive particlesare of magnesium stearate (that being a material that may be used but isnot preferred), we have found that an amount of 1.5 per cent by weightbased on the total weight of the powder is too great and causespremature segregation of the active particles from the carrierparticles. We believe that the same considerations apply in the case ofAerosil 200.

The present invention provides a powder for use in a dry powder inhaler,the powder including active particles and carrier particles for carryingthe active particles, the powder further including additive material onthe surfaces of the carrier particles to promote the release of theactive particles from the carrier particles on actuation of the inhaler,the powder being such that the active particles are not liable to bereleased from the carrier particles before actuation of the inhaler.

"Actuation of the inhaler" refers to the process during which a dose ofthe powder is removed from its rest position in the inhaler, usually bya patient inhaling. That step takes place after the powder has beenloaded into the inhaler ready for use.

In this specification we give many examples of powders for which theamount of the additive material is so small that the active particlesare not liable to be released from the carrier particles beforeactuation of the inhaler but are released during use of the inhaler. Ifit is desired to test whether or not the active particles of a powderare liable to be released from the carrier particles before actuation ofthe inhaler a test can be carried out. A suitable test is described atthe end of this specification; a powder whose post-vibration homogeneitymeasured as a percentage coefficient of variation, after being subjectedto the described test, is less than about 5% can be regarded asacceptable. In an example of the invention described below thecoefficient is about 2% which is excellent, whereas in an example alsodescribed below and employing 1.5% by weight of magnesium stearate thecoefficient is about 15% which is unacceptable.

The surface of a carrier particle is not usually smooth but hasasperities and clefts in its surface. The site of an asperity or of acleft is believed to be an area of high surface energy. The activeparticles are preferentially attracted to and adhere most strongly tothose high energy sites causing uneven and reduced deposition of theactive particles on the carrier surface. If an active particle adheresto a high energy site, it is subjected to a greater adhesion force thana particle at a lower energy site on the carrier particle and willtherefore be less likely to be able to leave the surface of the carrierparticle on actuation of the inhaler and be dispersed in the respiratorytract. It would therefore be highly advantageous to decrease the numberof those high energy sites available to the active particles.

Additive material is attracted to and adheres to the high energy siteson the surfaces of the carrier particles. On introduction of the activeparticles, many of the high energy sites are now occupied, and theactive particles therefore occupy the lower energy sites on the surfacesof the carrier particles. That results in the easier and more efficientrelease of the active particles in the airstream created on inhalation,thereby giving increased deposition of the active particles in thelungs.

However, as indicated above, it has been found that the addition of morethan a small amount of additive material is disadvantageous because ofthe adverse effect on the ability to process the mix during commercialmanufacture.

It is also advantageous for as little as possible of the additivematerial to reach the lungs on inhalation of the powder. Although theadditive material will most advantageously be one that is safe to inhaleinto the lungs, it is still preferred that only a very small proportion,if any, of the additive material reaches the lung, in particular thelower lung. The considerations that apply when selecting the additivematerial and other features of the powder are therefore different fromthe considerations when a third component is added to carrier and activematerial for certain other reasons, for example to improve absorption ofthe active material in the lung, in which case it would of course beadvantageous for as much as possible of the additive material in thepowder to reach the lung.

In the present case, as indicated above, there will be an optimum amountof additive material, which amount will depend on the chemicalcomposition and other properties of the additive material. However, itis thought that for most additives the amount of additive material inthe powder should be not more than 10%, more advantageously not morethan 5%, preferably not more than 4% and for most materials will be notmore than 2% or less by weight based on the weight of the powder. Incertain Examples described below the amount is about 1%.

Advantageously the additive material is an anti-adherent material andwill tend to decrease the cohesion between the active particles and thecarrier particles.

Advantageously the additive material is an anti-friction agent (glidant)and will give better flow of powder in the dry powder inhaler which willlead to better dose reproducibility from the inhaler.

Where reference is made to an anti-adherent material, or to ananti-friction agent, the reference is to include those materials whichwill tend to decrease the cohesion between the active particles and thecarrier particles, or which will tend to improve the flow of powder inthe inhaler, even though they may not usually be referred to as ananti-adherent material or an anti-friction agent. For example, leucineis an anti-adherent material as herein defined and is generally thoughtof as an anti-adherent material but lecithin is also an anti-adherentmaterial as herein defined, even though it is not generally thought ofas being anti-adherent, because it will tend to decrease the cohesionbetween the active particles and the carrier particles.

The carrier particles may be composed of any pharmacologically inertmaterial or combination of materials which is acceptable for inhalation.Advantageously, the carrier particles are composed of one or morecrystalline sugars; the carrier particles may be composed of one or moresugar alcohols or polyols. Preferably, the carrier particles areparticles of lactose.

Advantageously, substantially all (by weight) of the carrier particleshave a diameter which lies between 20 μm and 1000 μm, more preferably 50μm and 1000 μm. Preferably, the diameter of substantially all (byweight) of the carrier particles is less than 355 μm and lies between 20μm and 250 μm. Preferably at least 90% by weight of the carrierparticles have a diameter between from 60 μm to 180 μm. The relativelylarge diameter of the carrier particles improves the opportunity forother, smaller particles to become attached to the surfaces of thecarrier particles and to provide good flow and entrainmentcharacteristics and improved release of the active particles in theairways to increase deposition of the active particles in the lowerlung.

It will be understood that, throughout, the diameter of the particlesreferred to is the aerodynamic diameter of the particles.

Advantageously, the additive material consists of physiologicallyacceptable material. As already indicated, it is preferable for onlysmall amounts of additive material to reach the lower lung, and it isalso highly preferable for the additive material to be a material whichmay be safely inhaled into the lower lung where it may be absorbed intothe blood stream. That is especially important where the additivematerial is in the form of particles.

The additive material may include a combination of one or morematerials.

It will be appreciated that the chemical composition of the additivematerial is of particular importance.

Preferably the additive material is a naturally occurring animal orplant substance.

Advantageously the additive material includes one or more compoundsselected from amino acids and derivatives thereof, and peptides andpolypeptides having molecular weight from 0.25 to 1000 KDa, andderivatives thereof. Amino acids, peptides or polypeptides and theirderivatives are both physiologically acceptable and give acceptablerelease of the active particles on inhalation.

It is particularly advantageous for the additive material to comprise anamino acid. Amino acids have been found to give, when present in lowamounts in the powders as additive material, high respirable fraction ofthe active materials with little segregation of the powder and also withvery little of the amino acid being transported into the lower lung. Inrespect of leucine, a preferred amino acid, it is found that, forexample, for an average dose of powder only about 10 μg of leucine wouldreach the lower lung. The additive material may comprise one or more ofany of the following amino acids: leucine, isoleucine, lysine, valine,methionine, phenylalanine. The additive may be a salt or a derivative ofan amino acid, for example aspartame or acesulfame K. Preferably theadditive particles consist substantially of leucine, advantageouslyL-leucine. As indicated above, leucine has been found to giveparticularly efficient release of the active particles on inhalation.Whilst the L-form of the amino acids is used in Examples describedbelow, the D- and DL-forms may also be used.

The additive material may include one or more water soluble substances.This helps absorption of the substance by the body if the additivereaches the lower lung. The additive material may include dipolar ions,which may consist of zwitterions.

Alternatively, the additive material may comprise particles of aphospholipid or a derivative thereof. Lecithin has been found to be agood material for the additive material.

The additive material may include or consist of one or more surfaceactive materials, in particular materials that are surface active in thesolid state, which may be water soluble, for example lecithin, inparticular soya lecithin, or substantially water insoluble, for examplesolid state fatty acids such as lauric acid, palmitic acid, stearicacid, erucic acid, behenic acid, or derivatives (such as esters andsalts) thereof. Specific examples of such materials are: magnesiumstearate; sodium stearyl fumarate; sodium stearyl lactylate;phospatidylcholines, phosphatidylglycerols and other examples of naturaland synthetic lung surfactants; Liposomal formulations; lauric acid andits salts, for example, sodium lauryl sulphate, magnesium laurylsulphate; triglycerides such as Dynsan 118 and Cutina HR; and sugaresters in general.

Other possible additive materials include talc, titanium dioxide,aluminium dioxide, silicon dioxide and starch.

As indicated above, it is most important for the additive material to beadded in a small amount. For example, magnesium stearate is highlysurface active and should therefore be added in particularly smallamounts; phosphatidylcholines and phosphatidylglycerols on the otherhand are less active and can usefully be added in greater amounts; inrespect of leucine, which is still less active, an addition of 2% byweight leucine based on the weight of the powder gives good results inrespect of the respirable fraction of the active particles, lowsegregation and low amount of leucine reaching the lower lung; anaddition of a greater amount does not improve the results and inparticular does not significantly improve the respirable fraction andtherefore whilst even with 6% leucine a reasonable result is obtainedthat is not preferred since it results in an increased quantity ofadditive material being taken into the body and will adversely affectthe processing properties of the mix.

The additive material will often be added in particulate form but it maybe added in liquid or solid form and for some materials, especiallywhere it may not be easy to form particles of the material and/or wherethose particles should be especially small, it may be preferred to addthe material in a liquid, for example as a suspension or a solution.Even then, however, the additive material of the finished powder may bein particulate form. An alternative possibility, however, that is withinthe scope of the invention is to use an additive material which remainsliquid even in the final essentially particulate material which canstill be described as a "dry powder".

In some cases improved clinical benefits will be obtained where theadditive material is not in the form of particles of material. Inparticular, the additive material is less likely to leave the surface ofthe carrier particle and be transported into the lower lung.

Where the additive material of the finished powder is particulate, thenature of the particles may be significant. The additive particles maybe non-spherical in shape. In Examples 1 to 3 below, the additiveparticles are plate-like particles. Alternatively the additive particlesmay be angular for example prisms, or dendritic in shape. Additiveparticles which are non-spherical may be easier to remove from thesurfaces of the carrier particles than spherical, non-angular particlesand plate-like particles may give improved surface interaction andglidant action between the carrier particles.

The surface area of the additive particles is also thought to beimportant. The surface area of the additive particles, as measured usinggas absorption techniques, is preferably at least 5m² g⁻¹. In many casesit is found that additive material comprising small plate-like particlesis preferred.

Advantageously, at least 95% by weight of the additive particles have adiameter less than 150 μm, more advantageously less than 100 μm,preferably less than 50 μm. Preferably, the mass median diameter of theadditive particles is not more than about 10 μm. The additive particlespreferably have a mass median diameter less than the mass mediandiameter of the carrier particles and will usually have a mass mediandiameter of approximately between a tenth and a hundredth that of thecarrier particles. The diameter of the particles may be calculated bylaser diffraction or by another method by which the aerodynamic diameterof the particles can be determined.

The ratio in which the carrier particles, additive material and activeparticles are mixed will, of course, depend on the type of inhalerdevice used, the type of active particles used and the required dose. Asindicated above, the amount of additive material is of particularimportance. Advantageously the amount is in the range of from 0.1 to 10%by weight of the additive material based on the weight of the carrierparticles. For the examples given below, the powder preferably consistsof not less than 0.1% by weight of additive material based on the weightof the carrier particles and the powder preferably consists of at least0.1% by weight of active particles based on the weight of the powder.Furthermore, the carrier particles are preferably present in an amountof at least 90%, more preferably at least 95%, by weight based on theweight of the powder.

Conventional calculations of the extent of surface coverage of thecarrier particles by the additive material shows that for the preferredcarrier particles and preferred additive materials mixed in theirpreferred amounts, the amount of additive material is much more thanthat necessary to provide a monolayer coating of the carrier particle.For example, in the case of Example 1 described below, calculation showsthat a small fraction of a percent of leucine by weight is sufficient toprovide a monolayer coating, whereas 1% leucine by weight is employed.Furthermore, it is found that even with 1% leucine there is no "coating"of the carrier particles in the sense in which that word is normallyused in the art, namely to refer to a continuous envelope around thecarrier particle; rather inspection of the carrier particles under anelectron microscope shows much of the surface of each lactose particleremaining exposed with leucine particles covering only limited portionsof each lactose particle and forming a discontinuous covering on eachlactose particle. It is believed that the presence of such adiscontinuous covering, as opposed to a "coating" is an important andadvantageous feature of the present invention.

Preferably the additive material, whilst providing only a discontinuouscovering for the carrier particles, does saturate the surfaces of thecarrier particles in the sense that even if more additive material wereprovided substantially the same covering of the carrier particles wouldbe achieved. When the additive material in the finished powder isparticulate, some of the additive particles, either individually or asagglomerates, may act as carriers of active particles and may beseparate from or may separate from the surfaces of the carrier particleswith active particles attached to their surfaces. The dimensions of thecombined active particle and additive particle may still be within theoptimum values for good deposition in the lower lung. It is believedthat active particles which adhere to the additive particles on thecarrier particles may in some cases be preferentially released from thesurfaces of the carrier particles and thereafter be deposited in thelower lung without the additive particles.

Advantageously, the mass median diameter of the active particles is notmore than 10 μm, preferably not more than 5 μm. The particles thereforegive a good suspension on redispersion from the carrier particles andare delivered deep into the respiratory tract. Where the activeparticles are not spherical, the diameter of the particles may becalculated by laser diffraction or another method by which theaerodynamic diameter of the particles can be determined.

The active material referred to throughout the specification will bematerial of one or a mixture of pharmaceutical product(s). It will beunderstood that the term "active material" includes material which isbiologically active, in the sense that it is able to increase ordecrease the rate of a process in a biological environment. Thepharmaceutical products include those products which are usuallyadministered orally by inhalation for the treatment of disease such asrespiratory disease eg. β-agonists, salbutamol and its salts, salmeteroland its salts. Other pharmaceutical products which could be administeredusing a dry powder inhaler include peptides and polypeptides, such asDNase, leucotrienes and insulin.

The active particles may include a β₂ -agonist which may be terbutaline,a salt of terbutaline, for example terbutaline sulphate, or acombination thereof or may be salbutamol, a salt of salbutamol or acombination thereof. Salbutamol and its salts are widely used in thetreatment of respiratory disease. The active particles may be particlesof salbutamol sulphate. The active particles may be particles ofipatropium bromide.

The active particles may include a steroid, which may be beclomethasonedipropionate or may be Fluticasone. The active principle may include acromone which may be sodium cromoglycate or nedocromil. The activeprinciple may include a leukotriene receptor antagonist.

The active particles may include a carbohydrate, for example heparin.

According to the invention, there are provided particles for use in apowder as described above, the particles including carrier particles ofa first composition and of a size suitable for use in a dry powderinhaler and additive material of a second composition, the additivematerial being attached to the surfaces of the carrier particles.

In a general aspect, the invention also provides a powder for use in adry powder inhaler, the powder including active particles and carrierparticles for carrying the active particles wherein the powder furtherincludes additive material which is attached to the surfaces of thecarrier particles to promote the release of the active particles fromthe carrier particles.

According to the invention, there is also provided a method of producingparticles suitable for use as particles in dry powder inhalers, themethod including the step of mixing carrier particles of a size suitablefor use in dry powder inhalers with additive material which becomesattached to the surfaces of the carrier particles.

Additive material, which may be in liquid form or may comprise additiveparticles, or agglomerates of additive particles, may be introduced to asample of carrier particles, which may have been treated as describedbelow, and the mixture blended to allow the additive material to becomeattached to the surfaces of the carrier particles.

As indicated above, the exact ratio in which the carrier particles andthe additive particles are mixed will, of course, depend on the type ofdevice and the type of active particles used. Also as indicated above,the proportion of the additive material in the powder is of particularimportance.

The size of the carrier particles is an important factor in theefficiency of the inhaler, and an optimum, or near optimum, range ofsize of particles is preferably selected. Therefore, the methodadvantageously further includes the step of selecting from a sample ofcarrier particles an advantageous range of size of carrier particlesprior to the mixing step and, in the case where the additive material isin the form of particles when it is mixed with the carrier particles,preferably also includes the step of selecting from a sample of additiveparticles an advantageous range of size of additive particles prior tothe mixing step. The step of selecting an advantageous range of size maybe a sieving step.

Advantageously the additive material and the carrier particles are mixedfor between 0.1 hours and 0.5 hours. The particles may be mixed using atumbling blender (for example a Turbula Mixer).

Advantageously, the method further includes the step of treating thecarrier particles to dislodge small grains from the surfaces of thecarrier particles, without substantially changing the size of thecarrier particles during the treatment.

As indicated above, the surface of a carrier particle is not usuallysmooth but has asperities and clefts in the surface. As a result, thesurfaces have areas of high surface energy to which active particles arepreferentially attached. An active particle at a high energy site isless likely to be able to leave the surface and be dispersed in therespiratory tract than an active particle at a site of lower surfaceenergy. During the treatment referred to immediately above, asperitiesare removed as small grains, thus removing active sites associated withthe asperities.

Advantageously, the mixing step is prior to the treatment step. Theadditive material may therefore be added in the form of large particleswhich are broken into smaller particles during the treatment.Alternatively the treatment may be carried out before the addition ofthe additive material or, alternatively, after the addition of theadditive material and of the active particles.

Advantageously, the small grains become reattached to the surfaces ofthe carrier particles. The object of treating the carrier particles isto reduce the number of high energy sites on the carrier particlesurfaces, thus allowing an even deposition of active particles adheredon the surface with a force of adhesion such that dispersion of theactive particles during inhalation is efficient. While removingasperities as small grains removes those high energy sites associatedwith the asperities, the surfaces of the carrier particle have otherhigh energy sites, for example at the site of clefts, which sites arenot necessarily removed when the asperities are removed. It is highlyadvantageous to decrease the number of high energy sites.

The grains removed from the surface are small and thermodynamicallyunstable and are attracted to and adhere to the remaining high energysites on the surface of the carrier particles. Furthermore, where theadditive material is in the form of particles, the additive particlesare attracted to the high energy sites which therefore can becomesaturated. That situation is highly preferable as is described above. Onintroduction of the active particles, many of the high energy sites arealready occupied, and the active particles therefore occupy the lowerenergy sites on the carrier particle surface, or on the surface of theadditive particles. That results in the more efficient release of theactive particles in the airstream created on inhalation, thereby givingincreased deposition of the active particles in the lungs.

It will be understood that the term "carrier particles" refers to theparticles on which the small grains become attached. References tocarrier particles above, for example in respect of particle size, do nottherefore include those small grains.

Advantageously, the treatment step is a milling step. The milling causesasperities on the surfaces of the carrier particles to be dislodged assmall grains. Many of those small grains become reattached to thesurfaces of the carrier particles at areas of high energy as describedabove.

Preferably, the milling step is performed in a ball mill. The particlesmay be milled using plastics balls, or they may be milled using metalballs. Balls made of polypropylene material give less aggressivemilling, whilst steel balls confer more aggressive action. The mill maybe rotated at a speed of about 60 revolutions per minute. The mill mayalternatively be rotated at a speed less than 60 revolutions per minute,for example at a speed of less than about 20 revolutions per minute, orfor example a speed of about six revolutions per minute. That is a slowspeed for ball milling and results in the gentle removal of grains fromthe surfaces of the particles and little fracture of the particles.Widespread fracture of the particles, which occurs with aggressivemilling conditions, or at long milling times, may result in agglomeratesof fractured particles of carrier material.

Advantageously, the particles are milled for at least 0.25 hours,preferably the particles are milled for not longer than about 6 hours.That time has been found to be suitable when milling with balls madefrom plastics material. When using denser balls, or alternativematerials, shorter milling times may be used. Alternatively, a differentmilling technique may be used, for example using a re-circulated lowfluid energy mill, or other method that results in the removal of grainsfrom the surfaces of the particles, for example sieving, or cyclonetreatment.

As indicated above, the size of the particles is important and themethod may further include the step of selecting an advantageous rangeof size of particles prior to the treatment step.

Where reference is made to the size of the carrier particles beingsubstantially unchanged during the treatment, it will of course beunderstood that there will be some change in the size of the carrierparticles because portions of the particle are removed as small grainsduring the treatment. However, that change in size will not be as largeas that obtained when particles are milled in a conventional moreaggressive way. The gentle milling used in the treatment is referred toas "corrasion".

According to the invention, there is further provided a method ofproducing a powder for use in dry powder inhalers, the method includingthe steps of

(a) mixing carrier particles of a size suitable for use in dry powderinhalers with additive material such that the additive material becomesattached to the surfaces of the carrier particles.

(b) treating the carrier particles to dislodge small grains from thesurfaces of the carrier particles, without substantially changing thesize of the carrier particles during the treatment and

(c) mixing the treated particles obtained in step (b) with activeparticles such that active particles adhere to the surfaces of thecarrier particles and/or the additive material.

A satisfactory dry powder may also be obtained by mixing the activeparticles, the additive material and the carrier particles together inone step. Alternatively, the carrier particles may first be mixed withthe active particles, followed by mixing with the additive material.

Satisfactory dry powders may also be obtained by an alternative sequenceof steps. For example, the carrier particles, additive material andactive particles may be mixed together followed by a milling step.Alternatively, the carrier particles may first be milled before theaddition of additive material and active particles.

The invention also provides a method of producing a powder for use indry powder inhalers, the method including the steps of producingparticles as described above and mixing the particles with activeparticles such that active particles adhere to the surfaces of thecarrier particles and/or additive material.

According to the invention, there is also provided the use of additivematerial attached to the surfaces of carrier particles for carryingactive particles in a powder for use in a dry powder inhaler, for thepromotion of the release of active particles from the surfaces ofcarrier particles during inhalation, the powder being such that theactive particles are not liable to be released from the carrierparticles before actuation of the inhaler.

Embodiments of the invention will now be described by way of examplewith reference to the accompanying drawings:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a section through a carrier particle including additiveparticles on its surfaces;

FIG. 2 is a perspective view of a dry powder inhaler;

FIG. 3 is a sectional diagram of a twin stage impinger; and

FIGS. 4a & 4b show the effect of a milling treatment on the carrierparticle of FIG. 1.

EXAMPLE 1

Carrier particles were prepared by the following method. Meggle lactoseEP D30 (an α lactose monohydrate: pure crystalline milk sugar) was used.Lactose EP D30 has a useful particle size range and acceptable flowproperties.

(a) The lactose was sieved by the following method to give sampleshaving particles with a range of diameter from 90 μm to 125 μm.Successive samples of about 500 g, of lactose were sieved mechanicallyfor 40 minutes using successively woven wire stainless steel sieves ofaperture diameters 63 μm, 90 μm and 125 μm. The mesh was vibrated athigh speed on a Boulton rotary gyrator to reduce the binding of lactoseparticles to the mesh of the sieve. In order to try to improve theefficiency of the sieving process, after twenty minutes of the sievingprocess, the sieving was stopped and the sieve was removed and thepowder on the sieve was removed, the sieve brushed and the powderreplaced in the sieve from which it was removed. The sieve was thenreplaced and the sieving resumed.

200 g samples of the lactose EP D30 were taken from the particles whichhad passed through the 125 μm mesh sieve but had remained on the 90 μmsieve. Those particles could be considered to have a diameter between 90μm and 125 μm.

(b) Samples of lactose particles obtained in step (a) above were treatedby mixing the lactose particles with additive particles. 2 g of leucine(L-leucine α - aminoisocaproic acid) were added to 198 g of the lactoseparticles and mixed in a Turbula Mixer for approximately 15 minutes.

The leucine particles used were of a size such that 95% by weight of theparticles had a diameter of less than 150 μm. The mixture obtainedcontained approximately 1% leucine by weight.

FIG. 1 shows a representation of a particle 1 having asperities 2 andclefts 3. The additive particles 4 have become attached to the surfaceof the particle, mostly at the active sites on the surface. As can beseen from FIG. 1, the additive particles 4 cover only parts of thesurface of the particle, other parts of the surface remaining exposed.

(c) Samples of the particles including additive particles (obtained instep (b)) were mixed with active particles. 0.132 g of beclomethasonedipropionate (BDP) (mass median diameter 1.13 μm) were added to 29.868 gof the particles in a glass mortar. Each 30 g of mixture was blended.

The blending process with 0.132 g of BDP was repeated for a 29.868 gsample of lactose particles having a diameter between 90 μm and 125 μm(obtained in step (a)), but which had not been mixed with the additiveparticles, to give a comparative example.

(d) After one day, several samples each of 25 mg of mixture were takenfrom the container containing the particles including the additiveparticles and several samples each of 25 mg were taken from thecontainer containing the particles which had not been mixed with theadditive particles. Each sample was used to fill a respective one of anumber of size three capsules (size 3 transparent capsules obtained fromDavcaps of Hitchen, Herts., England). Those filled capsules were allowedto stand for one day to allow the decay of any accumulated electriccharge.

(e) The effect of the mixing of the lactose particles with additiveparticles was verified using a dry powder inhaler device and apharmacopoeial apparatus, for in vitro assessment of inhalerperformance.

(e)(i) FIG. 2 shows a view of a dry powder inhaler known as a Rotahaler(trade mark of Glaxo). The inhaler comprises an outer cylindrical barrel11 and an inner cylindrical barrel 12 of similar radius such that theinner barrel 12 is just able to fit inside the outer barrel 11. A mesh13 is attached across an end of the inner barrel 12 and a mouthpiece 14is attached around that end section of the inner barrel 12. The outerbarrel 11 is closed at one end by an end section 15 which contains inletslots 16 and an aperture 17. The inner barrel 12 also contains a fin 18along a length of the inner barrel at the open end, the fin extendingradially inwards from the internal surface of the inner barrel 12.

To operate the device, the inner barrel 12 is inserted into the open endof the outer barrel 11 such that the mouthpiece meets the outer barrel11 and the open end of the inner barrel is at the end section 15.Capsule 19 containing the mixture of carrier particles and activeparticles is inserted into the aperture 17 such that a portion of thecapsule 19 is held in the end section 15, and a portion of the capsule19 extends into the inner barrel 12. The outer barrel 11 is rotatedrelative to the inner barrel 12 and thus the fin 18 engages and breaksthe capsule. A patient inhales through the mouthpiece 14, air is drawninto the Rotahaler through the inlet slots 16, and the contents of thecapsule are discharged into the inner barrel as a cloud of powder andinhaled via the mouthpiece 14. The mesh 13 prevents the inhalation oflarge particles or of the broken capsule.

(e)(ii) FIG. 3 shows a diagrammatic arrangement of a twin stage impinger(TSI). The TSI is a two stage separation device used in the assessmentof oral inhalation devices. Stage one of the apparatus is shown to theright of the line AB in FIG. 3 and is a simulation of the upperrespiratory tract. To the left of that line is stage two which is asimulation of the lower respiratory tract.

The TSI comprises a mouth 21 which comprises a polydimethylsiloxaneadaptor, moulded to accept the mouthpiece of the inhaler device, uppertubing 22 and upper impinger 23 to simulate the upper respiratory tract,the upper impinger containing liquid 24, and lower tubing 25 and lowerimpinger 26 to simulate the lower respiratory tract, the lower impingercontaining liquid 27. The lower impinger 26 is connected via an outletpipe 28 to a pump 29 which draws air through the TSI apparatus at apredetermined rate. The base of the lower tubing 25 is below the levelof the liquid 27 such that all the air drawn through the TSI bubblesthrough the lower liquid 27. The liquid used in both the upper and lowerimpinger is a suitable solvent for the drug to be tested.

In use, the inhaler is placed in a mouth 21 of the TSI. Air is caused toflow through the apparatus by means of a pump 29 which is connected tostage two of the TSI. Air is sucked through the apparatus from the mouth21, flows through upper tubing 22 via the upper impinger 23 and thelower tubing 25 to the lower impinger 26 where it bubbles through liquid27 and exits the apparatus via outlet pipe 28. The liquid 24 in theupper impinger 23 traps any particle with a size such that it is unableto reach stage two of the TSI. Fine particles, which are the particlesable to penetrate to the lungs in the respiratory tract, are able topass into stage two of the TSI where they flow into the lower impingerliquid 27.

(f) 30 ml of solvent was put into the lower impinger 26 and 7 ml ofsolvent was put into the upper impinger 23. The lower tubing 25 wasarranged such that its lower end was below the level of the solvent inthe lower impinger 26. The pump 29 was adjusted to give an air flow rateof 60 liters per minute in the apparatus.

The Rotahaler was weighed when empty. One of the prepared capsules wasinserted into aperture 17 and the inhaler was reweighed. The mouthpiece14 of the inhaler was connected to the mouth 21 of the TSI, the outerbarrel 11 was rotated to break the capsule 19 and the pump was switchedon and timed for a period of ten seconds. The pump was then switched offand the Rotahaler was removed from the TSI, reweighed and the amount ofpowder lost from the inhaler calculated.

The remaining powder in the inhaler was washed into a flask for analysisand made up to 25 ml with solvent. The sections of the apparatus makingup stage one of the TSI were washed into a second flask and made up to50 ml with solvent. The sections making up the second stage of the TSIwere washed into a third flask and made up to 50 ml with solvent.

The other capsules were tested in the same way in a predetermined randomorder.

The contents of the flasks containing the washing from the stages of theTSI were assayed using High Performance Liquid Chromatography (HPLC)analysis for the content of BDP and compared against standard solutionscontaining 0.5 μg/ml and 1 μg/ml of BDP.

The percentage of BDP in each stage of TSI was calculated from thestandard response for each capsule and the mean for the treated samplesand the untreated samples could be calculated.

(g) Table 1 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the samples of the treated and theuntreated material. The respirable fraction (calculated as thepercentage of the total amount of drug emitted from the device, thatreaches stage two of the TSI) gives an indication of the proportion ofactive particles which would reach the deep lung in a patient. Thenumbers in brackets indicate the coefficient of variation for eachvalue.

                  TABLE 1                                                         ______________________________________                                                      no additive                                                                            1% leucine                                                           particles added                                                                           added                                               ______________________________________                                        Device          11.3    (19.7) 26.8    (6.8)                                  Stage 1                (4.7)          (3.1)                                   Stage 2                (40.5)         (9.0)                                   Respirable Fraction (%)                                                                           1.4                                                                              (37.5)         (6.8)                                   ______________________________________                                    

The results show that there has been an increase in the deposition ofactive particles in Stage two of the TSI: indicating an increaseddeposition in the deep lung for the samples containing leucine.

In addition, the coefficient of variation for each value for the treatedsamples was reduced: indicating increased reproducibility of the results(corresponding to improved dose uniformity of the administered drug).

EXAMPLE 2

(a) Samples of lactose particles having particles with a range ofdiameter from 90 μm to 125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in step (a) were treated bymixing the lactose particles with additive particles.

4 g of leucine (having 95% of weight of particles having a diameter lessthan 150 μm) were added to 196 g of lactose particles and blended asdescribed in Example 1 (b). The mixture obtained contained approximately2% leucine by weight.

(c) Samples of the particles obtained in step (b) including the additiveparticles were mixed with active particles as described above forExample 1 (c) and the samples were analysed as described in steps (d) to(f) for Example 1.

(d) Table 2 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the samples including the additiveparticles, and the respirable fraction. The figures for the samples fromExample 1 to which no additive particles were added are shown forcomparison.

                  TABLE 2                                                         ______________________________________                                                      no additive                                                                            2% leucine                                                           particles added                                                                           added                                               ______________________________________                                        Device          11.3    (19.7) 24.2    (7.0)                                  Stage 1                (4.7)          (2.0)                                   Stage 2                (40.5)         (14.9)                                  Respirable Fraction (%)                                                                           1.4                                                                              (37.5)         (11.9)                                  ______________________________________                                    

EXAMPLE 3

(a) Samples of carrier particles comprising lactose and 1% by weightleucine particles were prepared as described in steps (a) and (b) ofExample 1.

(b) Several samples of the carrier particles were each milled in aporcelain ball mill (Pascall Engineering Company) with 1200 ml of 20 mmplastics balls.

Samples (A), of which there were several, were milled at 60 rpm forthree hours.

Samples (B) were milled at 60 rpm for six hours.

Samples (C) and (D) were milled at 40 rpm for two hours and four hoursrespectively.

(c) The samples were mixed with active particles as described in Example1 (c) for the particles including the additive particles and analysed asdescribed in steps (d) to (f) for Example 1.

(d) Table 3 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the milled samples (A) to (B), andthe respirable fraction. The figures for the unmilled (1% leucine added)samples from Example 1 are shown for comparison.

The results show that there has been a significant increase in therespirable fraction, indicating increased deposition in the deep lungfor the milled samples.

                  TABLE 3                                                         ______________________________________                                                              lactose with 1% leucine and BDP                         unmilled      (A)     (B)      (C)   (D)                                      ______________________________________                                        Device  26.8      32.1    36.1   33.7  36.2                                                        (9.9)6.8)                                                                           (12.8)                                                                               (10.1)                                                                               (7.2)                                Stage 1           63.6                                                                              48.8                                                                                35.7    52.5                                                                                 41.2                                                    (7.2)3.1)                                                                           (6.7)   (4.8)                                                                                (4.5)                               Stage 2           7.5                                                                                21.8                                                                               30.8    13.6                                                                                 22.1                                                    (14.9).0)                                                                          (7.6)    (10.6)                                                                              (16.9)                               Respirable                                                                                   10.5                                                                                 30.8                                                                                46.3    20.5                                                                                 34.8                               fraction (%)                                                                               (6.8)                                                                                 (11.2)                                                                             (4.7)    (6.5)                                                                                (10.5)                              ______________________________________                                    

FIGS. 4a and 4b show the effect of the milling step. The shaded areas 5of the particle 1 represent the sections removed from the surface of theparticle as small grains during the milling. As shown in FIG. 4b, smallgrains 6 have become reattached to the surface of the particle, mostlyat active sites.

The effect on the flow characteristics of the milled particles of thepresence of leucine was investigated.

The Carr's index was measured for lactose (diameter 90 μm to 125 μm)samples (X), (Y) and (Z) where:

(X) contained milled lactose particles

(Y) contained lactose particles to which 1% leucine had been addedbefore milling

(Z) contained milled lactose particles to which 1% leucine had beenadded.

In each case, the milling was performed in a porcelain ball mill with1200 ml of 20 mm plastics balls. The mill was revolved at 60 rpm for sixhours.

Carr's index for a weight (W) of each sample was determined by measuringthe volume (V_(loose)) of weight (W) poured into a 250 cm³ measuringcylinder and tapping the cylinder to obtain constant volume of thesample (V_(tap)). The loose density and the tap density are calculatedas W/V_(loose) and W/V_(tap) respectively and Carr's index is calculatedfrom the tapped density and the loose density by the formula ##EQU1##

The Carr's index determined for each sample is given in table 4 below. ACarr's index of less than 25 is usually taken to indicate good flowcharacteristics; a Carr's index greater than 40 indicates poor flowcharacteristics.

                  TABLE 4                                                         ______________________________________                                               Sample                                                                              Carr's index                                                     ______________________________________                                               X     36.4                                                                    Y                    32.1                                                     Z                    35.6                                              ______________________________________                                    

The results indicate that the flow characteristics were improved by theaddition of leucine before milling (i.e. better flow).

EXAMPLE 4

(a) Samples of lactose having particles with a range of diameter from 90μm to 125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in (a) were treated by mixingthe lactose particles with additive particles.

1 g of soya lecithin particles were added to 199 g of the lactoseparticles and blended in a Turbula Mixer for 15 minutes. The mixtureobtained contained approximately 0.5% soya lecithin by weight.

(c) Several samples of the particles prepared in step 4 (b) above wereeach milled in a porcelain ball mill (Pascall Engineering Company) with1200 ml of 20 mm plastics balls. The samples were each milled at 60 rpmfor six hours.

(d) The milled samples obtained in step 4 (c) above and the unmilledsamples obtained in step 4 (b) above were each mixed with activeparticles as described in Example 1 (c) for the treated particles andanalysed as described in steps (d) to (f) for Example 1.

(e) Table 5 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the milled samples and for theunmilled samples, and the respirable fraction.

                  TABLE 5                                                         ______________________________________                                                    lactose with 0.5% soya lecithin and BDP                                       unmilled                                                                              milled                                                    ______________________________________                                        Device         22.9 (10.1)                                                                            29.5 (10.7)                                           Stage 1                              45.2 (12.5)                              Stage 2                              24.5 (11.1)                              Respirable                            35.3 (14.5)                             fraction (%)                                                                  ______________________________________                                    

The results show a significant increase in the respirable fraction,indicating increased deposition in the deep lung, for the milledsamples.

EXAMPLE 5

(a) Samples of lactose having particles within a range of diameter from90 μm to 125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in (a) were treated by mixingthe lactose particles with additive particles.

2 g of Aspartame particles were added to 198 g of the lactose particlesand blended in a Turbula Mixer for 15 minutes. The mixture obtainedcontained approximately 1% aspartame by weight.

(c) Several samples of the particles prepared in step 5 (b) above wereeach milled in a porcelain ball mill (Pascall Engineering company) with1200 ml of 20 mm plastics balls. The samples were each milled at 60 rpmfor six hours.

(d) The milled samples obtained in step 5 (c) above and the unmilledsamples obtained in step 5 (b) above were each mixed with activeparticles as described in Example 1 (c) for the particles including theadditive and analysed as described in steps (d) to (f) for Example 1.

(e) Table 6 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the milled samples and for theunmilled samples, and the respirable fraction.

                  TABLE 6                                                         ______________________________________                                                    lactose with 1% aspartame and BDP                                             unmilled                                                                              milled                                                    ______________________________________                                        Device        29.1 (16.0)                                                                             36.5 (10.7)                                           Stage 1                              41.4 (10.9)                              Stage 2                              19.8 (5.2)                               Respirable                           32.4 (6.1)                               fraction (%)                                                                  ______________________________________                                    

The results show a significant increase in the respirable fraction,indicating increased deposition in the deep lung for the milled samples.

EXAMPLE 6

(a) Samples of lactose having particles within a range of diameter from90 to 125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in 6 (a) were treated byadding additive particles to the lactose particles and milling thelactose-additive particle mixture.

Five different sets of samples containing five different amino acids asadditive materials were each prepared as follows:

2 g of additive particles were added to 198 g of the lactose particles(obtained in 6 (a)) in a 2.51 porcelain pot containing 1200 ml of 20 mmplastic balls. The pot was placed on a ball mill (Pascall EngineeringCompany) and milled at 60 rpm for six hours.

The five amino acids were Leucine, Lysine, Methionine, Phenylalinine andValine.

(c) The milled particles obtained in 6 (b) were mixed with activeparticles. 0.132 g of beclomethasone dipropionate (BDP) were added to29.868 g of the particles in a glass mortar. Each 30 g mixture wasblended.

(d) The powder samples obtained in 6 (c) were analysed using the TSI asdescribed in steps (d) to (f) for Example 1.

(e) Table 7 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the samples for each of the fivedifferent additive materials, and the respirable fraction. Forcomparison, a control formulation, prepared as described in steps (a) to(c) above but not including any additive material, was also analysed asin step (d) above.

                  TABLE 7                                                         ______________________________________                                                                     Meth- Phenyl-                                           Control                                                                               Leucine                                                                               Lysine                                                                                  ionine                                                                             aline                                                                              Valine                             ______________________________________                                        Device   33.0    36.1    33.9  31.5  31.0  40.8                               Stage 1               35.7                                                                                  52.1                                                                                45.1                                                                                            46.9                    Stage 2               30.8                                                                                  23.6                                                                                25.6                                                                                            19.6                    Respirable                                                                                          46.3                                                                                  31.0                                                                                36.2                                                                                           29.5                     Fraction (%)                                                                                  (11.0)                                                                            (4.7)                                                                                  (11.6)                                                                             (1.7)                                                                                           (7.7)                     ______________________________________                                    

EXAMPLE 7

(a) Samples of lactose having particles within a range of diameter from90 to 125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in 7 (a) were treated byadding particles of aspartame to the lactose particles and milling themixture as follows:

2 g of aspartame particles were added to 198 g of the lactose particles(obtained in 7 (a)) in a 2.51 porcelain pot containing 1200 ml of 20 mmplastics balls. The pot was placed on a ball mill (Pascall EngineeringCompany) and milled at 60 rpm for six hours.

(c) The milled particles obtained in 7 (b) were mixed with activeparticles as described in step (c) of Example 6.

(d) The powder samples obtained were analysed using the TSI as describedin steps (d) to (f) of Example 1.

(e) Table 8 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the samples, and the respirablefraction. The results of the control (as in Example 6) are shown forcomparison.

                  TABLE 8                                                         ______________________________________                                                    Control                                                                             Aspartame added                                             ______________________________________                                         Device       33.0    36.5                                                    Stage 1                              41.4                                     Stage 2                              19.8                                     Respirable                           32.4                                     Fraction (%)                       (6.1)                                      ______________________________________                                    

EXAMPLE 8

(a) Samples of lactose having particles within a range of diameter from90 to 125 μm were prepared as in Example 1(a) above.

(b) Samples of lactose particles obtained in 8(a) were treated by addingparticles of soya lecithin to the lactose particles and milling themixture as follows:

1 g of soya lecithin was added to 199 g of the lactose particles(obtained in 8 (a)) in a 2.51 porcelain pot containing 1200 ml of 20 mmplastics balls. The pot was placed on a ball mill (Pascall EngineeringCompany) and milled at 60 rpm for six hours.

(c) The milled particles obtained in 8 (b) were mixed with BDP asdescribed in step (c) of Example 6.

(d) The powder samples obtained were analysed using the TSI as describedin steps (d) to (f) of Example 1.

(e) Table 9 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the samples, and the respirablefraction. The results of the control (as in Example 6) are shown forcomparison.

                  TABLE 9                                                         ______________________________________                                                    Control                                                                             Lecithin added                                              ______________________________________                                        Device        33.0    44.8                                                    Stage 1                                  37.5                                 Stage 2                                  23.4                                 Respirable            25.5                                                                                             38.3                                 Fraction (%)        (11.0)                                                                                           (4.3)                                  ______________________________________                                    

EXAMPLE 9

(a) Samples of lactose having particles within a range of diameters from90 to 125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in 9 (a) were treated bymilling a mixture of the lactose particles and particles of wheatstarch. Milled samples of lactose and starch particles were prepared asfollows:

1 g of particles of wheat starch were added to 199 g of the lactoseparticles in a 2.51 porcelain pot containing 1200 ml of 20 mm plasticsballs. The pot was then placed on a ball mill (Pascall EngineeringCompany) and milled at 60 rpm for six hours.

(c) The milled particles obtained in 9 (b) were mixed with activeparticles. 0.264 g of salbutamol sulphate (SBS) were added to 29.736 gof the particles in a glass mortar. Each 30 g mixture was blended.

(d) The powder samples obtained in 9(c) were then analysed as describedin steps (d) to (f) of Example 1 but with the stages of the TSI beinganalysed for the SBS content.

Table 10 below shows the SBS content (in μg) recovered from the deviceand from each stage of the TSI as an average for the samples.

The respirable fraction (RF) is also shown and the number in bracketsindicates the coefficient of variation of the value.

                  TABLE 10                                                        ______________________________________                                                   Wheat starch                                                       ______________________________________                                               Device                                                                              94.7                                                                    Stage 1                                                                                               89.1                                                  Stage 2                                                                                               60.9                                                  RF (%)                                                                                                 40.8 (12.8)                                   ______________________________________                                    

EXAMPLE 10

(a) Samples of lactose having particles with a range of diameter from 90μm to 125 μm were prepared as in Example 1 (a) above.

(b) Additive material was added to the lactose particles as follows:

1 g of soya lecithin (90% by weight of particles less than 710 μm) wasdissolved in 10 g water and 10 g 1 MS (or in 20 g 95% ethanol) and addedto 199 g of the lactose particles in a high shear mixer.

The resulting mixture was blended for four minutes and then dried ontrays at 40° C. for 6 hours. The powder was screened through a 500 μmsieve.

The powder samples obtained contained approximately 0.5% soya lecithinby weight.

(c) The samples obtained in step 10 (b) above were each mixed withactive particles as described in Example 1 (c) for the treated particlesand analysed as described in steps (d) to (f) for Example 1.

(d) Table 11 below shows the BDP content (in μg) recovered from eachstage of the TSI as an average for the samples, and the respirablefraction.

                  TABLE 11                                                        ______________________________________                                                      no additive                                                                             0.5% soya                                                           material added                                                                            lecithin added                                      ______________________________________                                        Device          11.3 (19.7) 22.9 (10.1)                                       Stage 1                           71.9 (3.5)                                  Stage 2                        3.4 (11.4)0.5)                                 Respirable fraction (%)                                                                          1.4 (37.5)                                                                                4.4 (8.4)                                      ______________________________________                                    

The results show that there has been an increase in the deposition ofactive particles in Stage two of the TSI indicating an increaseddeposition in the deep lung for the samples containing soya lecithin.

EXAMPLE 11

Samples of milled lactose including leucine as additive material wereprepared and tested using the TSI to investigate the effect of usingdifferent dry powder inhaler devices and different drugs.

(i) The milled samples of lactose and leucine were prepared as follows:

(a) Samples of lactose having particles within a range of diameter from90 to 125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in 11 (a) were treated byadding leucine particles to the lactose particles and milling themixture.

2 g of leucine particles were added to 198 g of the lactose particles ina 2.51 pot which also contained 1200 ml of 20 mm plastics balls. The potwas then placed on a ball mill (Pascall Engineering Company) and milledat 60 rpm for six hours.

(ii) Several samples of the particles obtained in (i) were each mixedwith active particles as described below.

(a) 0.132 g of BDP were added to 29.868 g of the particles in a glassmortar and the mixture was blended.

(b) 0.132 g of SBS were added to 29.868 g of the particles in a glassmortar and the mixture was blended.

(c) 0.264 g of budesonide (BSN) were added to 29.736 g of the particlesin a glass mortar and the mixture was blended.

(iii) The powders obtained in (ii) were analysed using the TSI withthree different inhaler devices.

(a) Rotahaler (trade mark of Glaxo). The powder was analysed asdescribed in steps (d) to (f) for Example 1.

(b) Diskhaler (trade mark of Glaxo) Several samples of the powder, eachof 25 mg, were taken from the container. Each sample was used to fill ablister pocket in a package of commercial Becodisks (trade mark ofGlaxo), from which the commercial formulation had been removed. Therefilled blister packages were allowed to stand for one day to allow thedecay of any accumulated electrostatic charge. To evaluate theperformance of the powder in the Diskhaler, the blister package wasinserted into the Diskhaler and the mouthpiece of the inhaler wasconnected to the mouthpiece of the TSI. The analysis performed wasanalogous to that described in steps e(ii) to (f) for Example 1.

(c) Cyclohaler (manufactured by Pharbita B.V.) The method of analysingthe powders was analogous to that described in steps (d) to (f) forExample 1.

(iv) The analysis was repeated for each inhaler device using thecommercially available preparations of the active materials BDP, SBS andBSN (those preparations not containing the additive material and havingnot been treated as the powders tested in (iii)). For the Rotahalerthere was no commercial formulation of BSN available. A formulation wasprepared for comparison by preparing the powder as described abovewithout adding the leucine.

Table 12 below shows the active material (BDP, SBS, BSN) content (in μg)for the device and stages 1 and 2 of the TSI and the respirablefraction. The results shown are the average of the replicate testsperformed. The figures in brackets show the coefficient of variation.The results shown are in respect of the three different inhaler devices:Rotahaler (RH), Diskhaler (DH) and Cyclohaler (CH) for both thecommercial formulation (C) and the powder containing leucine as additive(L).

                  TABLE 12                                                        ______________________________________                                        In-  Active              De-  Stage                                                                               Stage                                                                             Respirable                            haler                                                                                        Component                                                                       Formulation                                                                               vice                                                                               1                                                                                 2                                       ______________________________________                                                                                Fraction                                 RH                                                                              BDP       C         25.6 64.0 14.9 14.9 (15.7)                           RH       BDP                            30.8                                                                                (4.7).3                         DH       BDP                            17.8                                                                                (5.1).8                         DH       BDP                       50.0--                                                                             38.9                                                                                (7.7).0                         RH       SBS                       110.0                                                                              40.3                                                                                (13.4)8                         RH       SBS                            60.0                                                                                (9.0).7                         DH       SBS                          74.7                                                                                  (7.9)39.4                       DH       SBS                          126.6                                                                                 (4.3)9.9                        CH       SBS                       170.8                                                                              36.0                                                                                (11.9)4                         CH       SBS                            74.6                                                                                (4.7).6                         RH       BSN                  47.7ne                                                                                  16.5                                                                                (5.5).0                         RH       BSN                            27.8                                                                                (10.2)3                         ______________________________________                                    

EXAMPLE 12

Samples of milled lactose including L-leucine as additive material atdifferent concentrations were prepared and tested using the TSI toinvestigate the effect of using different amounts of leucine.

(a) Samples of lactose having particles within a range of diameters from90-125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in (a) were treated by milling(corroding) the lactose particles with additive particles of L-leucine.

Appropriate weights of additive particles were added to appropriateweights of the lactose particles in a 2.51 porcelain pot, which alsocontained 200 ml of 3 mm steel balls. The pot was in each case thenplaced on a ball mill (Pascall Engineering Company) and milled at 60r.p.m. for 6 hours.

The weights of L-leucine (additive particles) and lactose particles inthe various samples were as detailed in Table 13 below:

                  TABLE 13                                                        ______________________________________                                        Weight of              % Concentration                                        additive           Weight of                                                                               of additive                                      particles     lactose particles                                                                         particles                                           ______________________________________                                         2 g       198 g       1.0%                                                    4 g                   196 g                                                                                             2.0%                               12 g                   188 g                                                                                             6.0%                               ______________________________________                                    

Several samples of each concentration were prepared.

Once the samples had been milled for the full 6 hours, the pots wereopened and the powders qualitatively assessed for evidence of caking.Caking is the appearance of non-redispersible material around the edgesof the pot and indicates poor processibility. It was noted that theextent of caking markedly increased as the L-leucine concentrationincreased from 1 to 6% Indeed, at a level of 6% L-leucine an extremelyhigh level of caking was observed, indicating that this mix could not beeffectively processed on a commercial scale.

(c) The milled samples obtained in (b) were then mixed with activeparticles of BDP as described in Example 1 (c).

(d) The milled samples mixed with the active particles obtained in (c)were then analysed as described in steps (d) to (f) for Example 1.

Table 14 below shows the BDP content (in μg) recovered from the deviceand from each stage of the TSI as an average of the replicateexperiments. The respirable fractions are also shown, and the figures inparenthesis denote the coefficients of variation. The results from acontrol formulation, prepared as described above but without any leucineparticles are also shown.

                  TABLE 14                                                        ______________________________________                                                     % Concentration of leucine                                                Control                                                                             1%         2%      6%                                          ______________________________________                                        Device     28.9    32.9       28.8  27.6                                                               (12.6)                                                                               (9.3)                                                                                 (2.7)                                 Stage 1       58.5         35.2                                                                                 27.9                                                                                 33.2                                                          (9.95)                                                                               (5.8)                                                                                 (8.2)                                 Stage 2       15.5         33.7                                                                                 43.3                                                                                 42.5                                                          (5.1)                                                                                 (2.9)                                                                                (6.7)                                 Respirable 20.9            49.0                                                                                 60.8                                                                                 56.2                                 fraction (%)                                                                               (11.5)                                                                                    (4.8)                                                                                 (2.4)                                                                                (6.4)                                 ______________________________________                                    

From the results shown above, it can be seen that no increase inrespirable fraction is obtained from increasing the concentration ofleucine above about 2 per cent. Increasing the concentration above about2 per cent does however adversely affect the ability to process the mixmaking it more difficult to process and at concentrations above 5 percent of leucine the mix becomes very much more difficult to process.

It is possible to make a quantitative assessment of the tendency of anyparticular powder to segregate. The following procedure can be adopted:

Thirteen interlocking plastic cylinders (internal diameter and heighteach approximately lcm) are assembled into a tower. The tower is thencarefully filled with a sample of the dry powder formulation for testingto produce a stack of powder approximately 13 cm high. The initialhomogeneity of the powder is then assessed by removing two,approximately 25 mg, samples of powder (noting the exact weights with ananalytical balance) from different points on the top surface of theuppermost cylinder. The uppermost cylinder is then removed from thestack by sliding it sideways. This procedure is then repeated until twosamples have been taken from each of the first ten cylinders in theoriginal stack.

The drug content of each powder sample is then determined using the sameHPLC analysis as employed for the TSI experiments, as described inExample 1 (f).

In order to determine the initial homogeneity, the quantity of drug (asdetermined by HPLC) in each sample is expressed as a percentage of theoriginal recorded weight of the powder sample. The values for all thesamples are then averaged to produce a mean value, and the coefficientof variation (CV) around this mean calculated. The coefficient ofvariation is a direct measure of the homogeneity of the mix.

The following procedure is then used to simulate the effects ofpharmaceutical processing conditions on the homogeneity of the drypowder formulations.

The cylinder tower, filled with dry powder formulation as describedabove, is attached to an electronic vibration unit. The instrument isset to a frequency of 50 Hz, with a vibrational amplitude of 2 g, and isswitched on to vibrate the cylinder containing the test powdervertically for 15 minutes. The purpose of the vibration is to subjectthe powder to treatment comparable to that which it might experienceduring commercial processing. The homogeneity of the dry powderformulation is then assessed using substantially the procedure describedabove. The vibrations will cause the powder to compact, with the resultthat, for example, the three uppermost cylinders may not contain anypowder at the end of the vibration. Such cylinders are not included inthe statistical analysis.

A powder, whose post-vibration homogeneity measured as a percentagecoefficient of variation, is less than about 5% can be regarded asacceptable and a coefficient of variation of 2% is excellent.

EXAMPLE 13

Samples of powder including L-leucine and magnesium stearate as additivematerials were prepared and the tendency of the powders to segregatequantitatively assessed. The details of the procedure adopted were asfollows:

(a) Samples of lactose having particles within a range of diameters from90-125 μm were prepared as in Example 1 (a) above.

(b) Samples of lactose particles obtained in (a) were treated by milling(corroding) the lactose particles with additive particles of a ternaryagent. The additive particles consisted of either L-leucine or magnesiumstearate.

Appropriate weights of additive particles were added to appropriateweights of the lactose particles in a 2.51 porcelain pot, which alsocontained 200 ml of 3 mm steel balls. The pot was in each case thenplaced on a ball mill (Pascall Engineering Company) and milled at 60r.p.m. for 6 hours.

The weights and types of additive particles and the weights of thelactose particles in the various tests were as detailed in Table 15below:

                  TABLE 15                                                        ______________________________________                                        Type of   Weight of  Weight of Concentration                                  additive      additive                                                                                 lactose                                                                               of additive                                  particles    particles                                                                               particles (g)                                                                               particles                                ______________________________________                                        Magnesium 3 g        197 g     1.5%                                           stearate                                                                      L-leucine       2 g            198 g                                                                                1.0%                                    L-leucine       4 g            196 g                                                                                2.0%                                    ______________________________________                                    

(c) The milled samples obtained in (b) were then mixed with activeparticles of BDP as described in Example 1 (c).

(d) The powders obtained from step (c) were then subjected to thesegregation test described above employing a tower of plastic cylinders.For each powder a first test was carried out without vibration to enablean initial homogeneity, expressed as a percentage coefficient ofvariation, to be determined; and a second test was carried out aftervibration to enable a post-vibration homogeneity, expressed again as apercentage coefficient of variation, to be determined. For the secondtest, it was found that the top three cylinders were substantially emptyafter vibration and therefore no results for those cylinders wereincluded in the statistical analysis.

The results of the tests are shown in Table 16 below:

                  TABLE 16                                                        ______________________________________                                                        Initial   Post-vibration                                                                     homogeneity                                    Additive particles                                                                                    (% CV)                                                                                      (% CV)                                  ______________________________________                                        1.5% Magnesium stearate                                                                       8.73      15.26                                               1.0% L-leucine                        4.07                                    2.0% L-leucine                        2.07                                    ______________________________________                                    

The poor initial homogeneity of the 1.5% magnesium stearate mixindicates the very strong tendency of the mix to segregate. Thepost-vibration results confirm the poor stability of the mix whensubjected to conditions comparable to those that might occur duringcommercial processing. Thus, even though a 1.5% magnesium stearate mixmay provide satisfactory results in terms of a respirable fraction, itdoes not meet the other important requirement of retaining homogeneityduring conditions that are comparable to those that might occur duringcommerical processing. In contrast the powders containing leucine, aswell as providing a satisfactory respirable fraction, had excellentinitial homogeneities and the homogeneities remained satisfactory evenafter intense vibration.

What is claimed is:
 1. A powder for use in a dry powder inhaler, thepowder comprising active particles and carrier particles for carryingthe active particles, the powder further comprising additive material onthe surfaces of the carrier particles to promote the release of theactive particles from the carrier particles on actuation of the inhaler,the powder comprising not more than 10% by weight of additive materialbased on the weight of the powder and the additive material comprisingan amino acid.
 2. A powder according to claim 1, wherein the amino acidis leucine.
 3. A powder according to claim 1, wherein the powdercomprises not more than 4% by weight of additive material based on theweight of the powder.
 4. A powder according to claim 3, wherein thepowder comprises not more than 2% by weight of additive material basedon the weight of the powder.
 5. A powder according to claim 1, whereinthe additive material is in the form of particles, the additiveparticles being attached to the surfaces of the carrier particles.
 6. Apowder for use in a dry powder inhaler, the powder comprising activeparticles and carrier particles for carrying the active particles, thepowder further comprising additive material on the surfaces of thecarrier particles to promote the release of the active particles fromthe carrier particles on actuation of the inhaler, wherein substantiallyall (by weight) of the carrier particles have a diameter which liesbetween 20 μ and 1000 μ and 95% of the additive material is in the formof particles having a diameter of less than 150 μ, the powder being suchthat the active particles are not liable to be released from the carrierparticles before actuation of the inhaler.
 7. A powder according toclaim 6, wherein the powder comprises not more than 5% by weight ofadditive material based on the weight of the powder.
 8. A powderaccording to claim 7, wherein the powder comprises not more than 2% byweight of additive material based on the weight of the powder.
 9. Apowder according to claim 6, wherein the carrier particles are comprisedof one or more crystalline sugars.
 10. A powder according to claim 9,wherein the carrier particles are particles of lactose.
 11. A powderaccording to claim 6, wherein substantially all (by weight) of thecarrier particles have a diameter which lies between 20 μm and 1000 μm.12. A powder according to claim 6, wherein the additive materialconsists of physiologically acceptable material.
 13. A powder accordingto claim 6, wherein the additive material comprises one or morecompounds selected from amino acids and derivatives thereof, andpeptides and polypeptides having a molecular weight from 0.25 to 1000KDa, and derivatives thereof.
 14. A powder according to claim 7, whereinthe additive material comprises an amino acid.
 15. A powder according toclaim 14, wherein the additive material consists substantially ofleucine.
 16. A powder according to claim 6, wherein the additivematerial comprises one or more water soluble materials.
 17. A powderaccording to claim 6, wherein the additive material is in the form ofparticles, the additive particles being attached to the surfaces of thecarrier particles.
 18. A powder according to claim 17, wherein at least95% by weight of the additive particles have a diameter less than 100μm.
 19. A powder according to claim 18, wherein the mass median diameterof the additive particles is not more than about 10 μm.
 20. A powderaccording to claim 6, wherein the powder consists of not loss than 0.1%by weight of additive particles based on the weight of the carrierparticles.
 21. A powder according to claim 6, wherein the additivematerial forms a discontinuous covering on the surfaces of the carrierparticles.
 22. A powder according to claim 20, wherein the additivematerial, whilst forming a discontinuous covering on the surfaces of thecarrier particles, saturates the surfaces of the carrier particles. 23.A powder according to claim 6, wherein the mass median diameter of theactive particles is not more than 10 μm.
 24. A powder according to claim6, wherein the active particles comprise a β₂ -agonist.
 25. A powderaccording to claim 24, wherein the active particles comprise salbutamol,a salt of salbutamol or a combination thereof.
 26. A powder according toclaim 6, wherein the active particles comprise beclomethasonedipropionate.
 27. Particles for use in a powder according to claim 6,the particles comprising carrier particles in a first composition and ofa size suitable for use in a dry powder inhaler and additive material ofa second composition, at least some of the additive material beingattached to the surface of the carrier particle.
 28. A powder for use ina dry powder inhaler, the powder comprising active particles and carrierparticles for carrying the active particles wherein the powder furtherincludes additive material which is attached to the surface of thecarrier particles to promote the release of the active particles fromthe carrier particles, the powder comprising not more than 10% by weightof additive material based on the weight of the powder.
 29. A method ofpromoting the release of active particles from the surfaces of carrierparticles during inhalation, comprising attaching an additive materialto the surfaces of carrier particles suitable for carrying activeparticles in a powder for use in a dry powder inhaler, and introducing apowder comprising said carrier particles with the additive material andactive particles into a dry powder inhaler, 95% of the additive materialbeing in the form of particles having a diameter which of less than150μ, substantially all (by weight) of the carrier particles having adiameter which lies between 20μ and 1000μ and the powder being such thatthe active particles are not liable to be released from the carrierparticles before actuation of the inhaler.
 30. A powder for use in a drypowder inhaler where in the powder is made according to a methodcomprising steps of:(a) mixing carrier particles of a size suitable foruse in dry powder inhaler with an amount of additive material such thatthe additive material becomes attached to the surfaces of the carrierparticles, and comprises not more than 10% by weight of additivematerial based on the weight of the powder; (b) treating the carrierparticles to dislodge small grains from the surfaces of the carrierparticles, without substantially changing the size of the carrierparticles during treatment; and (c) mixing the treated particles withactive particles such that active particles adhere to the surfaces ofthe carrier particles and/or the additive material.